Process for the preparation of benzopyran compounds

ABSTRACT

A process for preparing certain substituted benzopyran compounds is disclosed.

This application is a 371 of PCT/EP97/04328 Aug. 5, 1997.

The present invention relates to a process for preparing certainsubstituted benzopyran compounds which are useful as intermediates inthe preparation of a class of substituted benzopyran compounds known inthe art as therapeutic agents.

Substituted benzopyran compounds are known in the art. For example EP 0173 516-A discloses a class of substituted benzopyran compounds whichare described as compounds having activity as leukotriene antagonistsand 5-α-reductase inhibitors and useful in therapy in the treatment ofdiseases caused or exacerbated by leukotrienes or 5-α-reductaseactivity.

Various procedures for preparing such compounds are known in the art butthese suffer from certain disadvantages when considered for large scalecommercial application. The present invention therefore provides animproved route to substituted benzopyran compounds which gives thedesired compounds in good yield with relatively few process steps.

In a first aspect is therefore provided a process for the preparation ofa compound of structure (I): ##STR1## in which, R¹ is C₁₋₂₀ akyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, or a group of structure: ##STR2## each of whichmay be substituted by one or two substituents selected independentlyfrom C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl or C₂₋₂₀ alkynyl, up to 5 carbon atom(s)of which may optionally be replaced by oxygen atom(s), sulphur atom(s),halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s),naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s),carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxygroup(s), azido group(s) and/or nitro group(s);

R² is hydrogen or C₁₋₆ alkyl;

R³ is hydrogen, halogen, hydroxy, nitro, a group of general formula--COOR⁶ (wherein R⁶ represents hydrogen or C₁₋₆ alkyl), C₁₋₆ alkyl, C₁₋₆alkoxy or C₁₋₆ alkylthio; A is a single bond or a vinylene,propenyl-1-ene, butenyl-1-ene, butadienyl-1-ene or ethynylene groupoptionally being substituted by one, two or three C₁₋₁₀ alkyl and/orphenyl group(s); provided that the group formed by R¹ and A provides adouble or triple bond adjacent to the carbonyl group of the compound offormula (I);

R⁴ is OH and R⁵ is COCH₃ or R⁴ and R⁵ together with the phenyl ring towhich they are attached form a substituted benzopyran structure offormula (i): ##STR3## which comprises reaction of a compound of formula(II): ##STR4## in which R², R³, R⁴ and R⁵ are as defined in formula (I)with a compound of formula (III): ##STR5## in which R¹ and A are asdefined in formula (I) and X is a suitable group to allow metalinsertion in the presence of a metal catalyst and carbon monoxide, andoptionally thereafter,

forming a salt or N-oxide

converting the resulting compound of formula (I) into another compoundof formula (I)

Suitably the reaction is carried out at elevated temperature in thepresence of a metal catalyst. Metal catalysts include the carbonylcomplexes of Ni, Rh, Fe and Co or palladium complexes. A particularlyadvantageous aspect of the use of palladium complexes is that they canbe used in catalytic quantities, thereby avoiding the use of highlytoxic metal carbonyls, and enabling easier separation of the desiredproducts from metal residues. Suitable palladium catalysts includePd(OAc)₂, (Ph₃ P)₄ Pd, (Ph₃ P)₂ PdX₂ [e.g. X=I,Br,Cl], (bipyr)₂ Pd,bis(dibenzilidene acetone)Pd(0). The reaction can be carried out in thepresence of a reducing agent such as ammonium formate or hydrazinehydrate. Preferably the reaction can be carried out in the presence ofadditional ligands such as Ph₃ P, sulphonated-Ph₃ P, tri-tolylphosphine,bis(diisopropylphosphinyl)propane, polymer-bound-Ph₂ P, and1,1'-bis-(diphenylphosphino)ferrocene.

Preferably the reaction is carried out in the presence of a base.Suitable bases include Hunig's base, tri-n-butylamine, DBU, DABCO, orsodium acetate.

Suitably the reaction is carried out in a dipolar aprotic solvent, forexample in amidic solvents such as dimethylformamide,N-methyl-pyrrolidinone or dimethylacetamide, or in dimethyl sulphoxideor pyridine. In the case of catalysts with water soluble ligands such assulphonated-Ph₃ P the reaction can be carried out in water.

Suitably X is a group which allows metal insertion, for example halogenor triflate group.

It will be apparent to those skilled in the art that in order for metalinsertion to take place, the group formed by R¹ and A in compounds offormula (I) must provide a double or triple bond adjacent to thecarbonyl group of compounds of formula (I). In other words the carbonatom adjacent to the carbonyl group of compounds of formula (I) must bean sp² or sp hybridised carbon.

In particular, the reactions claimed herein are useful in thepreparation of compounds (I) in which R¹ and A form a group of formula(ii): ##STR6##

Preferably R² and R³ are both hydrogen.

Preferably R⁴ and R⁵ together form a group of formula (i) as definedabove such that R⁴ and R⁵ together with the phenyl ring to which theyare attached form a substituted benzopyran structure. When R⁴ is OH andR⁵ is COCH₃ the resulting compound of formula (I) can be converted tothe compound of formula (I) where R⁴ and R⁵ together form a group offormula (i) using the procedure disclosed in WO 94/12492.

Most preferably the process of the invention can be used to prepare thecompound Pranlukast, that is to say the compound4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyranor salt, hydrate or N-oxide thereof.

Compounds of formula (II) can be prepared by known procedures, forexample using the chemistry disclosed in EP 0 173 516-A.

Compounds of formula (III) can be prepared from the correspondingphenols using standard chemistry, for example as shown below: ##STR7##

1. Ph(CH₂)₄ Br, DMF, K₂ CO₃, heat.

The following examples serve to illustrate the invention.

Preparation of 4-(4-phenylbutoxy)halobenzene Derivatives

EXAMPLE 1 Preparation of 4-(4-Phenylbutoxy)bromobenzene

Potassium carbonate (7.6 g, 55.1 mmole), 4-bromophenol (5 g, 28.9 mmole)and 4-phenylbutylbromide (5.7 g, 26.8 mmole) were stirred indimethylformamide (30 ml) and heated at 100° C. for two hours. Thereaction mixture was quenched into water (150 ml) and the aqueous phaseextracted with ether (2×75 ml). The combined ethereal extracts waswashed with sodium hydroxide solution (˜0.5 M, 120 ml) and water (100ml). The organic layer was dried over sodium sulphate, filtered, andconcentrated in vacuo to an oil.

The crude product was purified using column chromatography (Stationaryphase: silica; Eluent: petroleum ether (60/80) and then 9:1 (v/v)petroleum ether (60/80): dichloromethane) to give4-(4-phenylbutoxy)bromobenzene (5.78 g, 71%).

NMR (CDCl₃) ppm, 1.72-1.82, 4H, m; 2.11-2.67, 2H, m; 3.85-3.89, 2H, m;6.71, 2H, d; 7.14, 5H, m; 7.31, 2H, d.

MS (E.I.) m/z (%) 65 (18), 91 (100), 104 (15), 117 (10), 132 (17), 172(16), 304 (3).

EXAMPLE 2 Preparation of 4-(4-phenylbutoxy)iodobenzene

Using the preparative procedure for 4-(4-phenylbutoxy)bromobenzene,except using 4-iodophenol in place of 4-bromophenol, gave4-(4phenylbutoxy)iodobenzene in 80% yield.

NMR (CDCl₃) ppm, 1.70-1.77, 4H, m; 2.61-2.66, 2H, m; 3.81-3.86, 2H, m;6.59, 2H, d; 7.11-7.28, 5H, m; 7.48, 2H, d.

MS (E.I.) m/z (%) 65 (12, 91 (100), 104 (8), 132 (8), 220 (35), 352 (6).

Carbonylation Procedure 1. Preparation of8-amido-4-oxo-2-(tetrazol-5-yl)-4H-1-benzopyran Derivatives

EXAMPLE 3a Preparation of4-Oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyranHemihydrate

A mixture of 4-(4-phenylbutoxy)bromobenzene (0.50 g, 1.64 mmole),8-amino-4-oxo-2-(tetrazol-5-yl)-4H-1-benzopyran (0.75 g, 3.28 mmole),bis-(triphenylphospine)palladium (II) chloride (0.135 g, 0.19 mmole) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.87 g, 5.74 mmole) was stirred inN-methylpyrrolidinone (10 ml) at 100-110° C. under an atmosphere ofcarbon monoxide at atmospheric pressure for 4.5 hours. The reactionmixture was diluted with water (15 ml) and acidified using concentratedhydrochloric acid (5 ml). The precipitate was filtered, washed withwater and methanol and then stirred in concentrated hydrochloric acid (8ml) to dissolve unreacted8-amino-4-oxo-2-(tetrazol-5-yl)-4H-1-benzopyran. The undissolved solidwas filtered, washed with concentrated hydrochloric (2×1.5 ml), water,then methanol. The damp cake was stirred with sodium acetate (0.15 g,1.83 mmole) in methanol (10 ml) and the solution filtered. Thesupernatant liquor was acidified with concentrated hydrochloric acid(0.2 ml), and the product filtered, washed with methanol and dried togive the title compound (422 mg, 53%).

NMR (DMSO-d₆) ppm, 1.70-1.86, 4H, m; 2.66-2.71, 2H, m; 4.10-4.14, 2H, m;7.09, 2H, d; 7.10, 1H, s; 7.18-7.33, 5H, m; 7.57, 1H, dd; 7.90, 1H, dd;8.03, 2H, d; 829, 1H, dd; 9.97, 1H, s.

MS (positive ion ionspray) m/z (%) 107 (100), 126, (10), 169 (13), 482(97), 963 (40).

MS (negative ion ionspray) m/z (%) 452 (11), 480 (100), 961 (10).

EXAMPLE 3b

Repeating carbonylation procedure 1 using 4-(4-phenylbutoxy)iodobenzenein place of 4-(4'-phenylbutoxy)bromobenzene gave the title compound in55% yield.

EXAMPLE 4a Preparation of6-chloro-4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran

Repeating carbonylation procedure 1 using8-amino-6-chloro-4-oxo-2-(tetrazol-5-yl)-4H-1-benzopyran in place of8-amino-4-oxo-2-(tetrazol-5-yl)-4H-1-benzopyran gave6-chloro-4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyranin 10% yield.

NMR (DMSO-d₆) ppm, 1.73-1.79, 4H, m; 2.64-2.70, 2H, m; 4.09, 2H, m;7.10, 2H, d; 7.15, 6H, m ; 7.80, 1H, d; 8.01, 1H, d; 8.43, 2H, d; 10.02,1H, s.

MS (positive ion ionspray) m/z (%) 516 (100).

MS (negative ion ionspray) m/z (%) 514 (100), 1029 (3).

EXAMPLE 4b

Repeating carbonylation procedure 1 using8-amino-6-chloro4-oxo-2-(tetrazol-5-yl)-4H-1-benzopyran and4-(4-phenylbutoxy)iodobenzene in place of8-amino-4-oxo-2(tetazol-5-yl)-4H-1-benzopyran and4-(4-phenylbutoxy)bromobenzene, gave6-chloro-4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)4H-1-benzopyranin 92% yield.

Carbonylation Procedure 2. Preparation of3-benzamido-2-hydroxyacetophenone Derivatives

EXAMPLE 5a Preparation of5-chloro-3-[4-(4-phenylbutoxy)benzoylamino]-2-hydroxy Acetophenone

4-(4-Phenylbutoxy)bromobenzene (0.50 g, 1.64 mmole),5-chloro-3-amino-2-hydroxyacetophenone (0.53 g, 2.89 mmole),bis(triphenylphosphine)palladium (II) chloride (0.10 g, 0.14 mmole) and1,8-diazabicyclo[5.4.0]undec-7ene (0.87 g, 5.74 mmole) was stirred inN-methylpyrrolidinone (10 ml) at 100-110° C. under an atmosphere ofcarbon monoxide at atmospheric pressure for 1.75 hours. The reactionmixture was cooled, quenched into water (50 ml) containing concentratedhydrochloric acid (5 ml) and extracted with dichloromethane (50 ml and2×25 ml). The combined extracts were treated with charcoal, dried(MgSO₄), concentrated in vacuo and the crude product stirred inisopropanol (30 ml) at 0-5° C. The precipitate was filtered, washed withchilled isopropanol and dried to give5-chloro-3-[4-(4-phenylbutoxy)benzoylamino]-2-hydroxyacetophenone (0.52g, 72%).

NMR (CDCl₃) ppm, 1.76-1.91, 4H, m ; 2.65, 3H, s; 2.68-2.73, 2H, m;4.01-4.06, 2H, m; 6.96, 2H, d; 7.16-7.34, 5H, m; 7.43, 1H, d; 7.85, 2H,d; 8.57, 1H, s; 8.83, 1H, d; 12.90, 1H, s.

MS (positive ion ionspray) m/z [M+H]⁺ 438.

MS (negative ion ionspray) m/z [M-H]⁻ 436.

EXAMPLE 5b

Repeating carbonylation procedure 2 using 4-(4-phenylbutoxy)iodobenzenein place of 4-(4phenylbutoxy)bromobenzene gave5-chloro-3-[4-(4-phenylbutoxy)benzoylamino]-2-hydroxyacetophenone in 82%yield.

EXAMPLE 6 Preparation of3-[4-(4-phenylbutoxy)benzoylamino]-2-hydroxyacetophenone

Repeating carbonylation procedure 2 using 3-amino-2-hydroxyacetophenoneand 4-(4-phenylbutoxy)iodobenzene in place of 3-amino-5-chloro-2-hydroxyacetophenone and 4-(4-phenylbutoxy)bromobenzene, gave3-[4-(4-phenylbutoxy)benzoylamino]-2-hydroxyacetophenone in 68% yield.

NMR (CDCl₃) ppm, 1.78-1.88, 4H, m; 2.66, 3H, s; 2.66-2.73, 2H, m;4.01-4.05, 2H, m; 6.93-6.99, 3H, m; 7.16-7.33, 5H, m; 7.48, 1H, dd;7.87, 2H, d; 8.58, 1H, s; 8.76, 1H, dd; 12.98, 1H, s.

MS (positive ion ionspray) m/z [M+H]⁺ 404.

MS (negative ion ionspray) m/z [M-H]⁻ 402.

We claim:
 1. A process for the preparation of a compound of structure(I): ##STR8## in which, R¹ is C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl,or a group of structure: ##STR9## each of which may be substituted byone or two substituents selected independently from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl or C₂₋₂₀ alkynyl, up to 5 carbon atom(s) of which may optionallybe replaced by oxygen atom(s), sulphur atom(s), halogen atom(s),nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalenering(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonylgroup(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s),azido group(s) and/or nitro group(s);R² is hydrogen or C₁₋₆ alkyl; R³ ishydrogen, halogen, hydroxy, nitro, a group of general formula --COOR⁶(wherein R⁶ represents hydrogen or C₁₋₆ alkyl), C₁₋₆ alkyl, C₁₋₆ alkoxyor C₁₋₆ alkylthio; A is a single bond or a vinylene, propenyl-1-ene,butenyl-1-ene, butadienyl-1-ene or ethynylene group optionally beingsubstituted by one, two or three C₁₋₁₀ alkyl and/or phenyl group(s);provided that the group formed by R¹ and A provides a double or triplebond adjacent to the carbonyl group of the compound of formula (I); R⁴is OH and R⁵ is COCH₃ or R⁴ and R⁵ together form a group of formula (i):##STR10## which comprises reaction of a compound of formula (II):##STR11## in which R², R³, R⁴ and R⁵ are as defined in formula (I) witha compound of formula (III): ##STR12## in which R¹ and A are as definedin formula (I) and X is halogen or a triflate group, and optionallythereafter, forming a salt or N-oxide.
 2. A process according to claim 1in which the catalyst is a palladium catalyst.
 3. A process claim 1 inwhich R¹ and A form a group of formula (ii): ##STR13##
 4. A processaccording to claim 1 in which R⁴ and R⁵ together form a group of formula(i):
 5. A process according to claim 1 in which the compound prepared is4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyranor salt, hydrate or N-oxide thereof.
 6. A process according claim 1 inwhich the compound prepared is3-[4-(phenylbutoxy)benzoylamino]-2-hydroxy-acetophenone.